Oct 14, 2016

Men being treated with prostate cancer therapies that reduce their testosterone levels are at greater risk of developing dementia within five years.

Reducing testosterone levels with androgen deprivation therapy (ADT) is a common treatment for prostate cancer.

A new retrospective study of patient medical records suggests that men with prostate cancer who are treated with testosterone-lowering drugs are twice as likely to develop dementia within five years as prostate cancer patients who are not.

Previous studies have linked the hormone treatment to an increased risk of depression and Alzheimer’s disease.

A new retrospective study of the health records of prostate cancer patients supports an association between androgen deprivation therapy and future risk of dementia.

Men with prostate cancer who are treated with testosterone-lowering drugs are twice as likely to develop dementia within five years in comparison with those who were not treated.

The study, by researchers at the Stanford University School of Medicine and the University of Pennsylvania Perelman School of Medicine, also demonstrates emerging techniques for extracting biomedical data from ordinary patient medical records.

In the new paper, the team expanded their work to include several other forms of dementia.

“When we published our last paper, a letter to the editor pointed out that Alzheimer’s is often confused with vascular dementia,” said Shah. “So instead of looking for Alzheimer’s and dementia separately, we decided to aggregate them into a higher-level category — all dementias and cognitive decline.”

Such aggregation could minimize the question of misdiagnosis, Shah said, and increase the sample size to provide more statistical power.

The team looked at deidentified records from Stanford Medicine’s clinical-research data warehouse for nearly 10,000 patients with prostate cancer. Of the 1,829 who received androgen deprivation therapy, 7.9 percent developed dementia within five years, compared with 3.5 percent of those not treated with ADT.

“The risk is real and, depending on the prior dementia history of the patient, we may want to consider alternative treatment, particularly in light of a recent prospective study from the U.K.,” said Shah.

That study, published in September in The New England Journal of Medicine, revealed that prostate cancer patients randomized to either active monitoring, surgery or radiation therapy all had the same risk of death from the cancer after 10 years. Ninety-nine percent of men in the study survived regardless of initial treatment. These startling results suggest that active monitoring of prostate cancer patients may be as good as early radical treatment and may cause fewer side effects.

The actual number of patients possibly at risk for dementia from androgen deprivation therapy is small, it makes sense when weighing the value of prescribing ADT to try to identify which prostate cancer patients might be vulnerable to dementia, said Shah.

The new study adds to a growing body of evidence supporting Stanford Medicine’s precision health approach, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

Nead and Shah cautioned that prostate cancer patients who are receiving ADT shouldn’t make changes to their medications without talking to their physicians.

“I was surprised at how ubiquitous the effects on all types of dementia were, but I would definitely not alter clinical care based on our results,” Nead said.

He added that he would like to see a prospective, randomized clinical trial to establish whether ADT can be more firmly linked to an increased risk of dementia and to help identify what kinds of patients might be vulnerable to that increased risk, he said.

He anticipates that checking for dementia risk in people treated with ADT will be part of future randomized, clinical trials that have a larger focus.

The new retrospective study of patient records took only a few weeks, said Shah.

“We are working to make such studies as simple as a Google search,” he said. “We were down to weeks in this one, and our current efforts, which are funded by the Dean’s Office, have gotten us to close to two to three days.”

In contrast, a prospective, randomized clinical trial to study the same question would probably require thousands of patients, years to complete and many millions of dollars, said Kenneth Mahaffey, MD, a Stanford professor of medicine who was not involved in the study.

I was surprised at how ubiquitous the effects on all types of dementia were.

And patient health record studies offer powerful ways to identify hypotheses about efficacy and safety that are worth further testing in clinical trials, said Mahaffey, who is vice chair of clinical research in Stanford’s Department of Medicine.

But the lack of randomization in health record studies means the results can be misleading, cautioned Mahaffey.

“This work is important,” he said, “but there are a number of examples of such retrospective studies where the results have been completely wrong.”

Retrospective studies of patient medical records aren’t meant to replace randomized clinical trials, said Shah. “If we had infinite funding, we’d do a trial for everything. But we don't have that,” he said. “These cheap, few-week studies can guide us where to point our clinical trial dollars.”

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Conclusions and Relevance
Androgen deprivation therapy in the treatment of prostate cancer may be associated with an increased risk of dementia. This finding should be further evaluated in prospective studies.

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